Chromosomal abnormalities are frequently associated with malignant diseases. In a number of instances, specific chromosomal translocations have been characterized, which generate fusion genes encoding proteins with oncogenic properties (Sawyers et al., Cell 64:337-350 (1991)).
Recently, the cloning of chromosomal translocations has led to identification of pathogenically relevant oncogenic fusion transcripts and proteins in specific subsets of acute nonlymphocytic leukemia (ANLL), such as promyelocytic leukemia-retinoic acid receptor alpha fusion gene (PML-RARα) in acute promyelocytic leukemia (FAB-M3 subtype), the acute myeloid leukemia 1-eight twenty one fusion gene (AML1-ETO) in ANLL with maturation (FAB-M2), and various mixed lineage leukemia (MLL) fusions in acute myelomonocytic and monocytic leukemias (FAB-M4 and -M5) (Melnick, A. & Licht, J. D., Blood 93, 3167-3215 (1999); Downing, J. R., Br. J Haematol. 106, 296-308 (1999); Rowley, J. D., Semin. Hematol. 36, 59-72 (1999); Look, A. T., Science 278, 1059-1064 (1997); Faretta, M., Di Croce, L. & Pelicci, P. G., Sem. Hematol. 38, 42-53 (2001)). Despite these significant advances, little is known about the genetic mechanisms underlying acute leukemias of the megakaryoblastic (platelet precursor) lineage (AMKL, FAB-M7) (Cripe, L. D, infra). Almost invariably, AMKL in non-Down syndrome infants and young children harbor the t(1;22)(p13;q13) translocation, in most cases as the sole cytogenetic abnormality (Carroll, A. et al; Lion, T. et al., and Bernstein, J. et al., infra). Phenotypically, AMKL presents de novo (i.e., without a so-called preleukemic stage), with a large leukemia cell mass, and frequent fibrosis of bone marrow and other organs. Progression is usually rapid despite therapy, with a median overall patient survival of only eight months. Thus, compositions and methods for the early and accurate diagnosis and treatment of leukemia, particularly AMKL, are needed.